The adenosine receptor (AR) family is an important class of physiologically and therapeutically relevant GPCRs that can benefit substantially from more selective drug targeting. Although all four AR subtypes are expressed in the mammalian heart, the wellknown protective effects of adenosine in this tissue are predominantly mediated by the adenosine A1 receptor (A1AR) subtype, especially under conditions of ischemia and reperfusion injury. Unfortunately, the transition of A1AR agonists into the clinic has been severely hindered because of high doses causing ontarget bradycardia, atrioventricular block, and hypotension.

As a consequence, clinical trials of AR agonists have had limited success because of the suboptimal dose of agonist that can be used. We have designed a novel bitopic A1AR ligand (MIPS746) - a hybrid molecule comprising adenosine linked to a positive allosteric modulator to engender biased signaling at the A1AR. This compound was able to act as cardioprotective agent without affecting heart rate, providing proof of concept that bitopic ligands can be designed as biased agonists to promote on-target efficacy without on-target side effects.

In an extension of this research we aim to further modify the allosteric component of this interesting bitopic ligand to obtain more drug-like derivatives. Reference: Valant et al. PNAS, 2014, 111, 4614-4619.